Salt of fused heterocyclic derivative and crystal thereof

ABSTRACT

An objective of the present invention is to improve the solubility of 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid. 
     The present invention provides 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyl-oxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid choline salt has excellent solubility and storage stability.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Stage of International Application No.PCT/JP2011/052719 filed Feb. 9, 2011, claiming priority based onJapanese Patent Application No. 2010-027806 filed Feb. 10, 2010, thecontents of all of which are incorporated herein by reference in theirentirety.

TECHNICAL FIELD

The present invention relates to a compound (chemical name:3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid choline salt; hereinafter, referred to as “compound (A)”)represented by the formula:

that has an antagonistic activity against gonadotropin releasinghormone, and is useful as a preventative or therapeutic agent for a sexhormone-dependent disease such as benign prostatic hypertrophy,hysteromyoma, endometriosis, metrofibroma, precocious puberty,amenorrhea, premenstrual syndrome, dysmenorrheal or the like.

BACKGROUND ART

A compound (hereinafter, referred to as “compound (B)”) represented bythe formula:

that has an antagonistic activity against gonadotropin releasinghormone, and is useful as a preventative or therapeutic agent for a sexhormone-dependent disease such as benign prostatic hypertrophy,hysteromyoma, endometriosis, metrofibroma, precocious puberty,amenorrhea, premenstrual syndrome, dysmenorrheal or the like isdisclosed in Patent reference 1. The publication merely contains generaldescriptions of salts as pharmacologically acceptable salts, and doesnot report specific salts of compound (B).

Patent reference 1: International Publication pamphlet 2007/046392

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

It has been confirmed by the diligent studies conducted by the presentinventors that compound (B) described in Patent reference 1 is amorphousor crystalline. One aspect of amorphous is that it is difficult to, forexample, isolate and purify in certain quality in the industrial scale,and accordingly crystals are more preferred as drug materials. However,as will be described in the test example below (saturation solubilitytest), the crystals of compound (B) have a solubility problem. The poorsolubility often causes problems in drug absorbability, and may requireingenuity in formulation with compound (B) used as a drug. Use ofcompound (B) as drug material thus requires improvements in solubility.

Means for Solving the Problems

The present inventors conducted intensive studies over the foregoingproblems, and found that3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid.choline salt has considerably high solubility and desirable storagestability, and thus represents a preferred compound as drug material.The present invention has been completed based on these findings.

That is, the present invention relates to:

(1) a compound represented by the above formula (A);

(2) the compound as described in the above (1), which is crystalline;

(3) the compound as described in the above (2), which has characteristicpeaks at diffraction angles (2θ(°)) of 7.1, 11.5, 19.4, 20.3, 21.5,22.0, 22.6, 23.5 and 26.2 in a powder X-ray diffraction diagram;

(4) the compound as described in the above (2), which has characteristicpeaks at chemical shift values (δ(ppm)) of 155.8, 149.8, 145.3, 118.0,113.7, 111.6, 110.3, 98.1, 69.8, 58.7, 57.1 and 55.5 in a ¹³Csolid-state NMR spectrum chart;

(5) the compound as described in the above (2), which has characteristicpeaks at chemical shift values (δ(ppm)) of −131.6, −145.2 and −151.8 ina ¹⁹F solid-state NMR spectrum chart;

(6) the compound as described in any one of the above (2) to (5), whichhas an endothermic peak at around 213° C. in a differential thermalanalysis chart;

(7) a pharmaceutical composition which comprises as an active ingredienta compound as described in any one of the above (1) to (6);

(8) the pharmaceutical composition as described in the above (7), whichis a gonadotropin releasing hormone antagonist;

(9) the pharmaceutical composition as described in the above (7), whichis an agent for the prevention or treatment of a sex hormone-dependentdisease, a reproduction regulator, a contraceptive, an ovulationinducing agent or an agent for the prevention of post-operativerecurrence of sex hormone-dependent cancers;

(10) a use of a compound as described in any one of the above (1) to (6)for the manufacture of an agent for the prevention or treatment of a sexhormone-dependent disease, a reproduction regulator, a contraceptive, anovulation inducing agent or an agent for the prevention ofpost-operative recurrence of sex hormone-dependent cancers;

(11) a method for preventing or treating a sex hormone-dependentdisease, a reproductive regulating method, a contraceptive method, anovulation-inducing method, or a method for prevention of post-operativerecurrence of sex hormone-dependent cancers, comprising administering aneffective amount of a compound as described in any one of the above (1)to (6); or the like.

Effect of the Invention

Compound (A) of the present invention has excellent solubility and oralabsorbability. Further, compound (A) has excellent crystallinity, andexcellent storage stability and fluidity. Compound (A) is thus easy tohandle, for example, in formulation.

BEST MODE FOR CARRYING OUT THE INVENTION

Compound (A) of the present invention can be prepared, for example,using the following method. Specifically, for example, a free compound(B), which can be produced by using the method described in Patentreference 1 or by using methods according to this method, is mixed withan equal amount (1.0 equivalent) or a small excess amount of cholinehydroxide in a suitable solvent. The mixture is then dissolved underheat, and the solvent is concentrated or added as appropriate, asrequired. Compound (A) precipitated upon cooling can then be isolated.Further, compound (A) may be purified by recrystallization using thesame or similar solvent.

The solvent may be any solvent, provided that it does not interfere withsalt formation. Examples of usable solvents include organic solvents,including alcohols such as methanol, ethanol, 1-propanol, 2-propanol,1-butanol and 2-butanol, ethers such as tetrahydrofuran and diisopropylether, and water. A mixed solvent of these also may be used.

Compound (A) of the present invention is extremely useful as an agentfor the prevention or treatment of sex hormone-dependent diseases suchas benign prostatic hypertrophy, hysteromyoma, endometriosis,metrofibroma, precocious puberty, amenorrhea, premenstrual syndrome,dysmenorrhea, polycystic ovary syndrome, lupus erythematosis, hirsutism,short stature, sleep disorders, acne, baldness, Alzheimer's disease,infertility, irritable bowel syndrome, prostate cancer, uterine cancer,ovary cancer, breast cancer and pituitary tumor, a reproductionregulator, a contraceptive, an ovulation inducing agent, an agent forthe prevention of post-operative recurrence of sex hormone-dependentcancers or the like.

Compound (A) according to the present invention may be appropriatelymixed with a pharmaceutical carrier used conventionally to prepare apharmaceutical composition.

The pharmaceutical carrier may be appropriately in combination accordingto a dosage form as described below. As the pharmaceutical carrier, forexample, excipients such as lactose or the like; lubricants such asmagnesium stearate or the like; disintegrators such ascarboxymethylcellulose or the like; binders such ashydroxypropylmethylcellulose or the like; surfactants such as Macrogolor the like; foamings such as sodium hydrogene carbonate or the like;dissolving aids such as cyclodextrin or the like; acidities such ascitric acid or the like; stabilizers such as sodium edentate or thelike; pH adjusters such as phosphoric acid salt or the like can beillustrated.

Examples of the dosage form of the pharmaceutical composition accordingto the present invention include orally-administered agents such aspowders, granules, fine granules, dry syrups, tablets, capsules and thelike; and parenterally-administered agents such as injections,poultices, suppositories and the like, and orally-administered agentsare preferable.

Preferably, the above formulations are prepared in such a way thatcompound (A) according to the present invention is administered in 0.1to 1,000 mg per day for adults in the case of orally-administeredagents, and in 0.01 to 100 mg per day for adults for injections.

EXAMPLES

The present invention is further illustrated in more detail by way ofthe following Examples and Test Examples. However, the present inventionis not limited thereto.

Example 1

Compound (A)

3-[2-Fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid (3.07 g) and a 46% choline hydroxide aqueous solution (1.64 g) weresuspended in a mixed solution of 1-propanol and water (about 1:1 volumeratio; 30 mL), and the mixture was heated and stirred for 15 min at 60°C. 1-Propanol (30 mL) was added to the mixture at 60° C., and themixture was stirred at room temperature for 1 hour, and for another onehour under ice-cooled conditions. After the precipitate was collected byfiltration, and washed twice with 1-propanol (1 mL). The resulting solidwas dried under reduced pressure at 40° C. to obtain compound (A) (2.93g). Further, this compound was heated and stirred at 60° C. in a mixedsolvent of 1-propanol and water (about 1:1 volume ratio; 30 mL), and1-propanol (30 mL) was added to the solution obtained after hotfiltration. The mixture was cooled to room temperature, and stirred for1 hour, and for another one hour under ice-cooled conditions. Theprecipitated crystals were collected by filtration, and washed twicewith a mixed solvent of 1-propanol and water (about 3:1 volume ratio; 1mL). The resulting crystals were air-dried for 4 days to obtain compound(A) (2.16 g).

¹H-NMR(DMSO-d₆)(δ(ppm)):3.10 (9H, s), 3.35-3.45 (2H, m), 3.70-3.90 (8H,m), 4.95 (2H, s), 5.47(1H, brs), 6.44 (1H, s), 6.85-6.95 (1H, m), 7.05(1H, d, J=11.5 Hz), 7.11 (1H, d, J=7.4 Hz), 7.48 (1H, dd, J=9.7 Hz, 19.5Hz),11.14(1H, brs)

The obtained compound (A) was measured with regard to powder X-raydiffraction, thermal analysis, ¹³C solid-state NMR spectrum and ¹⁹Fsolid-state NMR spectrum under the conditions below to obtain data.

For the powder X-ray diffraction, the crystals were ground with amortar, and measured with a powder X-ray diffraction apparatus X'PertPro MPD (Spectris plc, PANalytical Department) (reflection method; CuKαrays, tube voltage 45 kV, tube current 40 mA).

The resulting diffraction diagram is shown in FIG. 1, and diffractionangles)) (2θ(°)) and relative intensities (%) of peaks that had relativeintensities of about 20% or higher are shown in Table 1.

TABLE 1 Diffraction angle Relative intensity (2θ (°)) (%) 7.1 38 10.4 3211.5 48 13.9 31 14.1 29 14.3 24 15.5 31 16.1 23 16.4 20 17.4 22 19.0 3419.4 86 20.0 22 20.3 100 21.0 31 21.5 83 22.0 82 22.6 46 23.2 29 23.5 3925.1 22 26.2 57 26.7 22 28.3 29 29.6 27 30.1 27 31.2 22

For reasons related to the nature of data in powder X-ray diffraction,the 2θ values and the overall diffraction pattern are important for therecognition of crystal identity. It is common knowledge that therelative intensity in X-ray diffraction patterns fluctuates in a mannerthat depends on sample conditions and measurement conditions. It shouldbe noted that the 2θ values of diffraction patterns in powder X-raydiffraction may slightly fluctuate depending on sample conditions andmeasurement conditions.

For the thermal analysis, measurements were made using athermogravimetric differential thermal analyzer TG-DTA TG8120 (RigakuCorporation) (Heating rate: 10° C./min; reference material: aluminumoxide). The resulting chart is shown in FIG. 2.

Endothermic peak: around 213° C.

Note that the endothermic peak in thermal analysis may slightlyfluctuate depending on sample conditions and measurement conditions.

For the ¹³C solid-state NMR spectral measurement, a sample was chargedinto a 4-mm zirconia rotor, and measured with a Bruker Avance DRX500(rotation speed 10 kHz) using the CP/MAS technique. The resultingspectrum chart is shown in FIG. 3.

Note that the chemical shift values in the ¹³C solid-state NMR spectrummay slightly fluctuate depending on sample conditions and measurementconditions.

For the ¹⁹F solid-state NMR spectrum measurement, a sample was chargedinto a 2.5-mm zirconia rotor, and measured with a Bruker Avance III 400WideBore (rotation speed 30 kHz) using the MAS technique. The spectrumwas observed with reference to the external standard samplepolyvinylidene fluoride (PVDF) set to resonate at −91.2 ppm. Theresulting spectrum chart is shown in FIG. 5.

Note that the chemical shift values in the ¹⁹F solid-state NMR spectrummay slightly fluctuate depending on sample conditions and measurementconditions.

Example 2

Compound (A)

3-[2-Fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid (4.07 g), a 46% choline hydroxide aqueous solution (2.18 g),2-propanol (200 mL) and water (100 mL) were mixed, and heated for 15 minat 40° C. After removing the insoluble matter by filtration, theresulting solution was concentrated, and 2-propanol (80 mL) anddiisopropyl ether (80 mL) were added. The mixture was then stirred atroom temperature for about 1 hour, and then for about 4 hours underice-cooled conditions. The precipitated solid was collected, and driedat 90° C. overnight under reduced pressure (yield 3.59 g). A mixedsolution of ethanol and water (about 1:1 volume ratio; 25 mL) was thenadded to the resulting solid (3.56 g). The mixture was heated to 65° C.,and subjected to hot filtration after adding a mixed solution of ethanoland water (1:1 volume ratio; 10 mL) at the same temperature. Theresulting solution was stirred while being allowed to cool at roomtemperature for 2 hours, and further stirred at room temperature forabout 1 hour after adding ethanol (20 mL). The mixture was furtherstirred at room temperature for about 1 hour after adding ethanol (20mL), and further stirred overnight under ice-cooled conditions. Thesolid was collected from the mixture, washed with ethanol (5 mL), anddried by blowing nitrogen. The solid was further dried at 40° C.overnight under reduced pressure to obtain compound (A) (2.43 g). Theobtained compound (A) was measured for powder X-ray diffraction in thesame manner as in Example 1. The result confirmed that the compound (A)had the same crystal form observed in Example 1.

¹H-NMR(DMSO-d₆)(δ(ppm)):3.10 (9H, s), 3.35-3.45 (2H, m), 3.70-3.90 (8H,m), 4.96 (2H, s), 5.38 (1H, brs), 6.43 (1H, s), 6.85-6.95 (1H, m), 7.05(1H, d, J=11.5 Hz), 7.10 (1H, d, J=7.4 Hz), 7.47 (1H, dd, J=9.7 Hz, 19.5Hz),11.11 (1H, brs)

Comparative Example 1

Crystals of Compound (B)

Ethyl acetate (0.1 mL) was added to an amorphous solid of3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid (10 mg), and the suspension was heated to 50° C. The mixture wasthen dried by blowing nitrogen gas. The resulting solid was furtherheated to 70° C., and dried overnight under reduced pressure to obtaincrystals of compound (B) (10 mg). The obtained crystals of compound (B)were measured for powder X-ray diffraction in the same manner as inExample 1. The resulting diffraction diagram is shown in FIG. 4.

Comparative Example 2

Crystals of Compound (B)

3-[2-Fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid (0.69 g) was suspended in diisopropyl ether (10 mL), and themixture was stirred at 60° C. for 3 hours under heat. The mixture wasstirred at room temperature overnight, further for 1 hour underice-cooled conditions. The solid was collected by filtration, and driedunder reduced pressure to obtain crystals of compound (B) (0.65 g). Theobtained crystals of compound (B) were measured for powder X-raydiffraction in the same manner as in Example 1. The result confirmedthat the compound (B) had the same crystal form observed in ComparativeExample 1.

Comparative Example 3

-   3-[2-Fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic    acid.1/2N,N′-dibenzylethylenediamine salt (hereinafter, referred to    as “compound (C)”)

Acetonitrile (10 mL), N,N′-dibenzylethylenediamine (94.5 mg), and3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid (200 mg) were mixed. The mixture was suspended at about 60° C., andstirred while being allowed to cool at room temperature. The solid wascollected from the mixture by filtration, and dried at about 60° C.overnight under reduced pressure (247 mg).

¹H-NMR(DMSO-d₆)(δ(ppm)):2.83 (2H, s), 3.79 (3H, s), 3.80 (3H, s), 3.87(2H, s), 4.95 (2H, s), 6.85-6.95 (1H, m), 6.98 (1H, s), 7.09 (1H, d,J=11.5 Hz), 7.19 (1H, d, J=7.5 Hz), 7.25-7.55 (6H, m)

Test Example 1

Saturation Solubility Test

The compound (A) obtained in Example 2, the compound (B) crystalsobtained in Comparative Example 2, and the compound (C) obtained inComparative Example 3 were suspended in water, or in 1st fluid fordissolution test (hereinafter, referred to as “1st fluid”) or 2nd fluid(hereinafter, referred to as “2nd fluid”) described in the Reagents•TestSolutions for General Tests, the Japanese Pharmacopoeia, 15th Edition.The suspensions were incubated at 37° C. After filtering a part of thesuspensions, the concentrations of the resulting filtrates were measuredby HPLC, and the saturation solubilities were calculated and compared.The HPLC measurement conditions are as follows.

Measurement Conditions

-   Detector: Ultraviolet and visible spectrophotometer/wavelength: 225    nm-   Column: GL Science Inertsil ODS-3, 5 μm, 4.6×250 mm-   Column temperature: a constant temperature of around 35° C.-   Flow rate: 1.0 mL/min-   Mobile phase A: 10 mM potassium dihydrogen phosphate aqueous    solution adjusted to pH 5.5 with potassium hydroxide aqueous    solution-   Mobile phase B: Acetonitrile-   Mobile phase ratio 0 to 30 min: mobile phase A/mobile phase B=70/30

The saturation solubility values of compound (A), compound (B) crystals,and compound (C) in water, 1st fluid, and 2nd fluid are shown in Table2. In water, compound (A) had a saturation solubility about 600 timesand about 60 times higher than those of compound (B) crystals andcompound (C), respectively. The saturation solubility of compound (A) in1st fluid was about 30 times and about 2 times higher than those ofcompound (B) crystals and compound (C), respectively. In 2nd fluid, thesaturation solubility of compound (A) was about 10 times and about 70times higher than those of compound (B) crystals and compound (C),respectively. These results thus confirmed significant improvements inthe solubility of compound (A) over compound (B) crystals and compound(C).

TABLE 2 The crystals of the The compound (B) compound (C) The compound(A) obtained in obtained in obtained in Comparative Comparative Example2 Example 2 Example 3 Water 4165 7 68 1st fluid 4 0.14 2 2nd fluid 3738367 52 Unit: μg/mL

Test Example 2

Assay for Oral Absorbability

1) Preparation of Sample for Drug Concentration Measurement byAdministration through Tail Vein

SD rats (Charles River, male, 7 weeks of age, 170 to 210 g) were used asexperimental animals after fasting the rats overnight.N,N-dimethylacetamide (0.2 mL), saline (0.798 mL) and 2N—NaOH (0.002 mL)were added in these amounts with respect to 1 mg of the compound (B) toprepare a 1.0 mg/mL solution. The solution was then administered in a 1mL/kg dose (1 mg/kg) through the tail vein under no anesthesia (3samples). The intravenous administration through tail was performedusing a 26G injection needle and a 1 mL syringe. Blood was collectedthrough the subclavian veins after 2, 15, 60, 120, 240 and 360 minutesfrom the intravenous administration through tail. The blood wascentrifuged, and the plasma was used as a sample for blood drugconcentration measurement.

2) Preparation of Sample for Drug Concentration Measurement by OralAdministration

SD rats (Charles River, male, 7 weeks of age, 220 to 290 g) were used asexperimental animals after fasting the rats overnight. A 0.5%methylcellulose aqueous solution (5 mL) was added with respect to 3 mgof compound (A) or compound (B) (in terms of a free compound) to preparea 0.6 mg/mL drug solution. Each solution was orally administered to therats in a 5 mL/kg dose (3 mg/kg) (3 samples each). The oraladministration was performed using a rat sonde and a 2.5-mL syringe.Blood was collected through the subclavian veins under no anesthesiaafter 15, 30, 60, 120, 240, 360 and 480 minutes from the oraladministration. The blood was centrifuged, and the blood plasma was usedas a sample for blood drug concentration measurement.

3) Drug Concentration Measurement

A suitable internal standard substance solution (0.1 mL) was added tothe blood plasma (0.025 mL) obtained in 1) and 2) using an ordinarymethod. Then, acetonitrile (0.875 mL) was added to remove the protein.After centrifugation, the supernatant (0.005 mL) was injected toLC-MS/MS. Blood plasma drug concentration was measured using theLC-MS/MS technique under the conditions below. Note that the standardcurve was created by appropriately adding an internal standard substanceand a target substance to a blank blood plasma (0.05 mL) using anordinary method, followed by the foregoing procedures.

-   LC-   Device: Agilent 1100-   Column: Capcellpak MGIII 5 μm 4.6×50 mm-   Mobile phase A: 10 mM ammonium acetate aqueous solution-   Mobile phase B: Acetonitrile-   (Mobile phase ratios are presented in Table 3)-   Column temperature: 40° C.-   Flow rate: 0.5 mL/min-   MS/MS-   Device: API-4000-   Ionization method: ESI (Turbo Ion Spray)

TABLE 3 Time (minutes) A (%) B (%) 0.0 90 10 3.0 90 10 4.0 10 90 7.0 1090 7.1 90 10 12.0 90 10

The bioavailability of the compound (A) was about 59%, and desirableoral absorbability was confirmed. Further, the maximum drugconcentration time (Tmax) was 35 min in the compound (A), compared to200 min in the compound (B), and because the compound (A) was quicklyabsorbed after the administration, a fast onset of action is expected.

Bioavailability (%) was calculated from the value of the area under theblood drug concentration-time curve determined by using a WinNonlinProfessional (Pharsight Corporation) from the blood drug concentrationat each time point obtained as above after the intravenousadministration of the compound (B) through tail and the oraladministration of the compound (A) or the compound (B).

Test Example 3

Stability Test

The compound (A) obtained in Example 2 was stored under 90° C. openconditions to examine stability. In stability measurement, the purity ofa sample was measured by HPLC at the initial point and after 8 days, andthe results were compared. The HPLC measurement conditions are asfollows.

Measurement Conditions

-   Detector: Ultraviolet and visible spectrophotometer/wavelength: 225    nm-   Column: GL Science Inertsil ODS-3, 5 μm, 4.6×250 mm-   Column temperature: Constant temperature around 35° C.-   Flow rate: 1.0 mL/min-   Mobile phase A: 10 mM potassium dihydrogen phosphate aqueous    solution adjusted to pH 5.5 with potassium hydroxide aqueous    solution-   Mobile phase B: Acetonitrile-   (Mobile phase ratios are shown in Table 4)-   Area measurement range: 54 minutes from the start of the analysis.    Areas of the peaks in the blank were excluded from the calculations.

The measurement results are shown in Table 5.

TABLE 4 Time (minutes) A (%) B (%) 0 70 30 20 70 30 40 30 70 60 30 7060.1 70 30 80 70 30

TABLE 5 The compound (A) obtained in Example 2 Measurement point Initialpoint After 8 days Purity (%) 99.6 99.6

As described above, the results of Test Examples 1 to 3 show that thecompound (A) of the present invention has excellent solubility, oralabsorbability and storage stability, and thus represents an excellentcompound capable of solving the problems relating to the physicalproperties of the free compound (B).

INDUSTRIAL APPLICABILITY

The compound (A) according to the present invention has excellentsolubility and other desirable physical properties, and is useful asdrug material, and suited for the industrial production of drugs.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a powder X-ray diffraction diagram of compound (A) obtained inExample 1. The vertical axis shows X-ray diffraction intensity (Counts);and the horizontal axis shows diffraction angle (2θ(°)).

FIG. 2 is a diagram representing the TG-DTA measurement of compound (A)obtained in Example 1. The vertical axis (left) shows weight (%) in athermogravimetric (TG) curve; the vertical axis (right) shows heat flux(μv) in a differential thermal analysis (DTA) curve; and the horizontalaxis shows temperature (° C.).

FIG. 3 is a ¹³C solid-state NMR spectrum chart of compound (A) obtainedin Example 1. The vertical axis shows intensity; and the horizontal axisshows chemical shift value (δ(ppm)).

FIG. 4 is a powder X-ray diffraction diagram of compound (B) obtained inComparative Example 1. The vertical axis shows X-ray diffractionintensity (Counts); and the horizontal axis shows diffraction angle(2θ(°)).

FIG. 5 is a ¹⁹F solid-state NMR spectrum chart of compound (A) obtainedin Example 1. The vertical axis shows intensity; and the horizontal axisshows chemical shift value (δ(ppm)).

The invention claimed is:
 1. A compound represented by the formula:


2. The compound as claimed in claim 1, which is crystalline.
 3. Thecompound as claimed in claim 2, which has characteristic peaks atdiffraction angles (2 θ( °)) of 7.1, 11.5, 19.4, 20.3, 21.5, 22.0, 22.6,23.5 and 26.2 in a powder X-ray diffraction diagram.
 4. The compound asclaimed in claim 2, which has characteristic peaks at chemical shiftvalues (δ(ppm)) of 155.8, 149.8, 145.3, 118.0, 113.7, 111.6, 110.3,98.1, 69.8, 58.7, 57.1 and 55.5 in a ¹³C solid-state NMR spectrum chart.5. The compound as claimed in claim 2, which has characteristic peaks atchemical shift values (δ(ppm)) of −131.6, −145.2 and −151.8 in a ¹⁹Fsolid-state NMR spectrum chart.
 6. A pharmaceutical composition whichcomprises as an active ingredient a compound as claimed in claim 1.